I am heterozygous for MTR A2756G and homozygous for MTRR A664A. Not sure how to interpret that. I've tried fairly high doses of b12 before but not sure if it helped very much. How much methylb12 (sublingually) would I need to take to help mitigate that mutation? I know this is all very complicated but I have been trying very hard for a very long time to resolve this issue without any results to show for it.

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MTR is an upregulation that makes you use up a lot more methyl groups and MTRR homozygous means you are not recycling methyl groups well at all. This is Heartfixer's take on it:

"MTR combines 5-methyl folate and homocysteine to form methionine and tetrahydrofolate (THF). More specifically, MTR removes a methyl group from 5-methyl folate, then tacks it on to homocysteine to form methionine. In the process 5-methyl folate is converted back to THF.

The MTR A2756G defect is an up regulation. The enzyme is always on, grabbing every homocysteine and 5-methyl folate molecule that it can get its hands on, processing them to methionine and THF. Methyl-B12 is required for normal function of MTR, and with each spin of the MTR enzyme, one molecule of methyl-B12 is degraded.

MTRR (Methionine Synthase Reductase) serves the needs of MTR, regenerating methyl-B12 from available methyl donors and B12. Without methyl-B12, MTR cannot convert homocysteine in to methionine. Needed downstream methyl donors such as SAMe will not be generated. Methylation fails, so does your biochemistry, and there goes your health.

When the MTR A2756G defect is present, MTR is always on, using up methyl-B12 faster than MTRR can regenerate it. The consequence is deficient methyl-B12. B12 blood levels may be normal, but as levels of methyl-B12 will be low, normal B12 physiology cannot be carried out. Homocysteine levels will typically be elevated. SAMe generation and methylation in general will be compromised. We can treat the MTR up regulation by:
a. Supplementing you with methyl-B12.
b. Measures designed to increase formation of methyl-B12.
c. We can also bypass the dysfunctional MTR step by stimulating the “backdoor” BHMT reaction, which converts homocysteine directly in to methionine (more on this approach later).
d. When we do not need to limit sulfur intake (CBS normal or under control with low urine sulfate readings) we can simply supplement you with SAMe, our most important methyl donor, which is otherwise formed from the methionine generated by the MTR/MTRR reaction. "

Without knowing your COMT status or CBS status, hard to know your best avenue to proceed. Have you posted your full snps here anywhere?

If you are CBS clean you can do his SAMe backdoor fix. If you are not (like me) you will need to push on other methyl donors, like MB12, I would think.

If you have significant COMT snps, you may have some anxiety/dopamine issues that get triggered in trying to work this out.

On the face of it, MB12 supplementation should be needed in spades, especially if you are trying to push methylfolate dosages (and you might not want to do that right now, given your MTRR/MTR status. I don't know enough to say.)

I found that I needed the MB12 shots at 1 mg every other day to start to feel better from Freddd's protocol. I was going downhill on it for the first two months because I was pushing folate higher and higher without getting enough methyl groups in. I'm backing down on my folate right now, to 1.6 mg or maybe even lower, depending on how slippery my neurotransmitter situation continues to be (I can feel normal one day and anxious the next. I want to be more stable than that.)

Sue, I was just looking into this as possibly why I didn't respond well to SMP the first couple of times after an initial very encouraging startup. I have +/+ for MTRR A66G & MTRR A664A (slowing down the recycle of B12) and a +/- for MTR A2756G (speeding up the use of B12). I'm assuming that means I probably need much more MB12 per Mfolate instead of equal doses that I was taking. The last time it was taking only MB12 (and not Mfolate) that slowly pulled me out of the funk. I assumed my feeling bad was due to detox because of my CBS 699T +/- but now wondering.

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@sregan that's exactly where my thinking is at now too. My physician wanted me to scale waaay back on mfolate (from 4000 mcg/day to 400mcg) and start the mb12 shots. I was resistant to it because of all the high-dosage folate successes happening here, but I think my doc was right and I'm scaling back my methylfolate, though not quite that far back. I was at 1600 and I'm going down to 1200mcg today. I'll keep dropping it until my anxiety stabilizes. (I don't mind the euphoria end of the neurotransmitter disregulation nearly so much, but that should probably be dampened down as well, sadly.)

i added my mutations to my signature. I have tried sam-e in the past but I feel like it stopped working after a couple weeks. I do feel like I have too much dopamine when I increase my methylfolate dosage. Can this be mitigated by upping the b12? I don't know.

You have both CBS mutations. You don't want to do SAM-E. Bad things happen that I have run out of mental energy to remember at this moment.

You have the two COMTs I have too. Those muddy the decision making around what type of b-12 to take. But from my experience, you might do just fine on MB12 at higher doses than you're currently taking.

I vastly overestimated how much MB12 I was absorbing buccally. That was one problem for me. I thought I was titrating up 1:1 but at some point I forgot to calculate the absorption rate in and was taking 4000mcg folate and 5000mcg MB12 (and 3-5000mcg Adb12) without realizing I was probably only absorbing about 1200 mcg MB12, if that. Hugely out of balance.

You and I have quite similar snps, so I wonder if my doctor's advice wouldn't stand just as well for you. I know I'm on the wrong thread to be saying this, but I'd try going low on the folate, 400 mcg, and titrating up on the MB12 until you feel an increase in energy and a decrease in neurotransmitter wackiness. Once you start feeling good, then maybe move up on both the folate and mb12, but being mindful of the ratio between the two that made you feel better and trying to stick to that.

I love the simplicity of Freddd's protocol, but without knowing what his snps are, I'm thinking we can't know if that *really* will work for everyone. I do think the advice to start low and go slow (which I was unable to stick with) is important.

I went downhill significantly over the last two months by getting so over-folated and under-methylated.

To be accurate, I was also accidentally overbreathing with a meditation practice that exacerbated other types of hyperventilation I was unaware I was doing (sighing, yawning, sniffing b/c of allergies) and had messed up my CO2/oxygen levels to a shocking degree. I'm getting that back in balance with Buteyko breathing exercises.

In my defense, I did have some low potassium symptoms to sort out in the beginning too, which muddied my understanding of what was causing what.

I'm still far from clear, but I'm definitely getting a better picture. The surge in energy and mental clarity that came with b-12 shots made me realize that I should be feeling better on this protocol, not worse, even if it's only 3 steps forward two steps back, as Whodathunkit says.

I don't think I will try to titrate up to high doses of methylfolate until I am consistently feeling better on the low dose and until I have a clearer idea of what ratio of Mb12 to folate works best for me.

About the timing of MFolate relative to MB12. Freddd mentions he takes his folate first so it absorbs then the Mb12 something about getting twice as much time for the Folate to work this way..

"methylfolate orally reaching a serum peak in an hour and sublingual b12 that is absorbed noticeably in 5 minutes"

But I thought we were all putting the MB12 under our upper lip for 30-60 minutes to get the most absorption out of it. Seems that matches the absorption rate of the orally taken MFolate to me. Unless the idea is to have ALL the folate in place before the MB12 hits?

@sregan I'm taking my folate and then putting the B12 in gum. I do this early AM and midday. And the B12 lasts a long time, at least 2 hours. It's still bright pink, so I guess it's still absorbing. Seems to be working fine. Maybe that quote from Fred means B12 has begun to be absorbed in 5 minutes.

My acne is out of control today, but I've consistently been taking 20 mg of MTHF to 5-10 mg mb12, and taking 10 mg adb12 every few days (I was taking it every day but learned it was unnecessary). I'm starting to cut back on folate in my diet in case that is fuelling my need for methylfolate, although I did have avocado at lunch today. How quickly would eating natural folate have an impact on my need for MTHF?

Also, does anyone know what effect LCF would have? Would that decrease or increase the need for folate? I've been afraid to add it in, as I haven't yet eliminated the low folate symptoms, or at least what I'm assuming are low folate: acne, peeling skin, some mouth sores.

How quickly would eating natural folate have an impact on my need for MTHF?

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I can't answer that, but I can tell you that eliminating natural folate had an almost immediate effect on me. As I was involved in intensive detox at the time, I initially believed it was due to the braking effect of cooked veg. I now think it was rather about exponentially increased methylation. After a few days I needed to stop the MTHF altogether for a few days, experienced no deficiency symptoms from that.

@mgd1972
Just thought I would let you know that my pimples, peeling skin and mouth sores have responded to zinc carnosine and P5P. I eat quite a bit of food folate. A green shake in AM with dandelion, romaine, cucumber, carrot, beet, apple (for extra pectin to feed gut bugs and soothe gastritis), sometimes a few cranberries or other berries, although they can make things too acidic for my ulcer at times (which seems to be healing slowly). I also have a few other veggies during day, perhaps broccoli or asparagus, or a bit more lettuce. Sweet potato is a staple food now and seems to be very soothing. I tested so low in vitamins A and C that I feel I need to keep these foods in rotation. I'm Not positive that this much folate does not rock my boat to some degree, but I do seem to crave these foods for whatever reason and I try to pay attention to my body as best as if can.

I take 3 or 4 zinc carnosine daily in divided doses, plus extra zinc since I tested low and out of ratio with copper. I take about 50 mg P5P ( also tested low in that). I do less methylfolate than most here, only 4-6 mg daily and less b 12 also at about 2 mg. everything I take is in divided doses throughout the day.

I'm still not out of the woods but I am making slow, fairly steady progress on my overall healing. It is quite slow tho. I am compound hetero, age 57.

I do have great energy most days and have put on muscle. I eat a high protein diet now and also take Multi T/D by Pure Encapsulations and plenty of glutamine, some lysine, DGL, a good hunk (480 mg) of magnesium, plus n acetyl glucosamine, lecithin, K2 (both mk4 and 7), fish and/or flax oil and plenty of ghee which I get from Pure Indian Foods. It is always a lovely, bright yellow.

I'm under the care of a functional med doc who monitors things every 6 mos.
Hope something here is helpful. Kim

@mgd1972
Just thought I would let you know that my pimples, peeling skin and mouth sores have responded to zinc carnosine and P5P. I eat quite a bit of food folate. A green shake in AM with dandelion, romaine, cucumber, carrot, beet, apple (for extra pectin to feed gut bugs and soothe gastritis), sometimes a few cranberries or other berries, although they can make things too acidic for my ulcer at times (which seems to be healing slowly). I also have a few other veggies during day, perhaps broccoli or asparagus, or a bit more lettuce. Sweet potato is a staple food now and seems to be very soothing. I tested so low in vitamins A and C that I feel I need to keep these foods in rotation. I'm Not positive that this much folate does not rock my boat to some degree, but I do seem to crave these foods for whatever reason and I try to pay attention to my body as best as if can.

I take 3 or 4 zinc carnosine daily in divided doses, plus extra zinc since I tested low and out of ratio with copper. I take about 50 mg P5P ( also tested low in that). I do less methylfolate than most here, only 4-6 mg daily and less b 12 also at about 2 mg. everything I take is in divided doses throughout the day.

I'm still not out of the woods but I am making slow, fairly steady progress on my overall healing. It is quite slow tho. I am compound hetero, age 57.

I do have great energy most days and have put on muscle. I eat a high protein diet now and also take Multi T/D by Pure Encapsulations and plenty of glutamine, some lysine, DGL, a good hunk (480 mg) of magnesium, plus n acetyl glucosamine, lecithin, K2 (both mk4 and 7), fish and/or flax oil and plenty of ghee which I get from Pure Indian Foods. It is always a lovely, bright yellow.

I'm under the care of a functional med doc who monitors things every 6 mos.
Hope something here is helpful. Kim

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Thanks for this. What is the dosage of your zinc? I have been taking 30 mg of zinc (hvp chelate) once a day, but I will try increasing.

Thanks for this. What is the dosage of your zinc? I have been taking 30 mg of zinc (hvp chelate) once a day, but I will try increasing.

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Hi @mgd1972,
I currently take 62 mg total zinc. 32 mg is zinc carnosine (pepzin GI). I refer to this as "sticky zinc" as the mechanism of action is apparently that the bonding of zinc to carnosine causes it to adhere to the stomach lining and create healing for things like gastritis and ulcers. There is no question that at least my gastritis feels better since adding this in early June.

15 mg comes from the Multi T/D as picolinate, and 15 I take as zinc glycinate, which supposedly gets into cells the best.

I have no idea how much of this I am actually absorbing, but I go next week for a standard blood draw to look at copper/ zinc ratio to get a rough idea, then in September I am due for my next Nutreval. My doc is approaching this cautiously.

Something inside is telling me I need more as I crave raw, red meat and my iron levels are ok. I will post more as I have more info.

Maybe this is understood but I want to make sure. Passages like the ones below talk about ramping up MFolate but don't mention ramping up the B12 along side. Is this assumed? Freddd mentioned in my last quote (of his below) that 100mcg of B12 is all that is needed for up to 30mg of MFolate.

So my confusion. I'm getting the idea, finally, that one needs to ramp up on the MFolate to get any substantial benefit from SMP. And others who are posting what they are taking seem to be taking almost as much B12 as MFolate.

I was wondering if the extra folate needed suddenly when symptoms occur must be accompanied by more B12? I might assume that would indicate that most likely it's for more methylation. But maybe not? The body might use the extra Folate in other ways?

"If you want to get rid of low folate symptoms and inflammation try 4mg of l-methylfolate or so each 4-6 hours Typically it will start turning around within a few hours and after a day or 3 you should know for sure. Now it is possible you are one of those who needs 30mg a day to make any headway but that is rare without folic acid or folinic acid or large amounts of vegetable folate.

Try 8mg before you go to bed tonight. Metafolin has no side effects different from sugar pills. That is what the Deplin study says at doses up to 30mg/day. Best results are at 15 and 30mg daily. That is what all my experience says. The people who take tiny doses have terrible reactions and think it is because of so much folate instead of so little. They have even worse responses with 200 mcg of folinic and 200mcg of mfolate. Wow do they get hit. That is because of a double whammy paradoxical folate deficiency. Without the folate you are wasting your money and wasting 90% of the b12. You could get equally bad results from 500mcg of b12.

Try it cautiously, 4 mg and then 4rmg in couple of more hours to avoid possible stomach distress or take 8mg and some food and go for it. You could be a new man in 2 days.

After you get rid of all the folate deficiency symptoms, then is the time to adjust other things. Doing it otherwise is bass akwards.

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I would suggest 200mcg doses of L-methylfolate, 4 per day, because of the short half-life. 100mcg combined absorbed AdoCbl/MeCbl plus the Methylfoalte will typically unblock partial methylation block and break methyltrap within hours.

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100mcg absorbed AdoCbl/MeCbl is all that is needed to start the need for even 30mg of Metafolin. These items are not tied together in any ratio. It is more the B1, B2 and B3 and maybe other things that drive the relative needs for methylfolate and potassium. Also, the amount of l-methylfolate a person needs also depends on how well their body handles folic acid, folinic acid and veggie folates.

FWIW, I asked freddd yesterday about his relative levels of mb12 and mfolate after he posted that he was taking 30 mg of b12 a day. He appears to currently be dosing 2-1 MB12 to Mfolate.

@Freddd, what levels of mfolate are you taking with 30 mgs mb12?
I take 4.8mg 3 times a day for a total of just under 15mg daily. In the Deplin studies the most effective doses were 15mg and 30 mg a day. Since bringing B1, B2 and B3 down to the most effective levels that don't overdrive need for methylfolate and potassium, getting consistent on taking 3 doses EVERY day, I haven't had a folate insufficiency episode. However, even when I wasn't getting that much absorbed during the CL trial, I still needed the same amount of folate. The linkage between folate need and quantity of MeCbl or AdoCbl is very loose.

Maybe this is understood but I want to make sure. Passages like the ones below talk about ramping up MFolate but don't mention ramping up the B12 along side. Is this assumed? Freddd mentioned in my last quote (of his below) that 100mcg of B12 is all that is needed for up to 30mg of MFolate.

So my confusion. I'm getting the idea, finally, that one needs to ramp up on the MFolate to get any substantial benefit from SMP. And others who are posting what they are taking seem to be taking almost as much B12 as MFolate.

I was wondering if the extra folate needed suddenly when symptoms occur must be accompanied by more B12? I might assume that would indicate that most likely it's for more methylation. But maybe not? The body might use the extra Folate in other ways?

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Hi Sregan,

For me the need for methylfolate appeared immediately. However, it wasn't available so I had no idea why I was getting all those other symptoms as many things healed. For a lot of people the 100mcg absorbed, just enough to go into diffusion distribution, enough to raise ones serum cobalamin level to 10,000-20,000 pg/ml for 30 minutes. That is enough for widespread body healing and needs a lot of methylfolate. I haven't found any reliable increase for folate with an increase in b12. So in this recent trial where I couldn't get enough CL methyl b12 into my cns and I slide backwards with a much lower absorbed dose, when I went back to 30mg of injections a day, I needed exactly the same 15mg/day as I had on a much smaller amount. Potassium is very similar. Those have remained stable plus or minus 200mg of potassium a day over the range in these last few months. And it is all titrated to effectiveness, not theoretical considerations.

ADDED in edit

MeCbl is recycled by the body. It acts more as a catalyst than as a methyl donor. MeCbl handles the methylgroup and passes it on. Then it gets another. This recycling system is what lets HyCbl be processed to MeCbl BUT it doesn't bring it's own chips into the game so it has to borrow to ante up.. So it has to borrow that first methyl group. So instead of function > recycle > function, you get recycle > function > recycle. It becomes a competitor for methyl groups when it starts as HyCbl or CyCbl. To me this looks like a limited capacity recycling system. Approximately 99% of HyCbl, AdoCbl, CyCbl and MeCbl is excreted by the kidneys unchanged. It's that 1% used over and over that undergoes changes. MeCbl is destroyed by toxins, oxidized by cyanide, nitrous oxide and glutathione and others and arsenic and bismuth are aggressive methyl grabbers,

@sregan I'm taking my folate and then putting the B12 in gum. I do this early AM and midday. And the B12 lasts a long time, at least 2 hours. It's still bright pink, so I guess it's still absorbing. Seems to be working fine. Maybe that quote from Fred means B12 has begun to be absorbed in 5 minutes.

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Exactly! When I was terribly low on MeCbl I could feel the first feel the first few mcg absorbed in the frst 5 minutes since they made a relatively huge difference to what had been there. I has been 10+ years since I could feel the MeCbl in 5 minutes. We feel differences, not steady starts. I can't feel a thing from SAM-e or MeCbl or any of them any more. That doesn't mean the are not working, that means an equilibrium has been attained. If stop b12 or SAM- or whatever for a few days I can feel them all over again. It gets more difficult when only changes in symptoms tip you off as to what is going on but that happens to everybody who succeeds in getting to an equilibrium with these vitamins. They are only felt when serum level is increasing out of insufficiency and new things are activated. They are STARTUP sensation. The sensation of being in steady state healing is whatever the healing itself feels like, painful before pain relieving in the neurology. The startup effects all go away. That's why I call them startup effects. There are only present at the start.

Huh. I wonder if this is why so many people have a reaction to mineral make up with bismuth oxychloride in it. I used to use a brand that I loved, loved, loved the way it looked, but over time I got so sensitive to it that I couldn't wear it any more. Interestingly, around the time I started wearing it was around the time I started going really in the tank, energically speaking.

i just recently started taking high doses of methylfolate (16mg/day) and the first couple days in gave me a lot of mental energy but now I am EXHAUSTED. I have been sleeping over 12 hours a day and even after than I feel I could go back to bed. Is this healing taking place?

Also, the other day I felt like I couldn't catch my breath and think I had a panic attack and proceeded to fall asleep for 4 hours. This seems uncharacteristic of a normal panic attack. What could be going on here?